DESCRIPTION: (Applicant's Abstract) In humans the use of heroin, cocaine and methamphetamine often becomes habit forming. This is thought to be due, in part, to their strong positive reinforcing properties. Similar behavior has also been observed in rats and mice who will repeatedly self-administer opiates or psychostimulants if given the opportunity. Efforts to identify the neuroanatomical substrates that involve an animal's repeated administration of an opiate or a psychostimulant have relied on lesioning of specific brain nuclei, microdialysis and neuro-pharmacological manipulations. The current interpretation in this field is that the mesocorticolimbic dopamine neurons are, to a large extent, responsible for mediating many of the positive reinforcing properties of abused drugs. Originating in the ventral tegmental area these dopamine neurons project primarily to the nucleus accumbens, frontal cortex, olfactory tubercle, amygdala, and septum. The interest in the ventral tegmental area's input to the nucleus accumbens is based on the profound effects that lesioning and neuropharmacological manipulation of dopamine levels in the nucleus accumbens have on an animal's behavioral response to opiates and psychostimulants. Although dopamine is known to interact with a small number of proteins in the nucleus accumbens, including members of the dopamine receptor family and the dopamine transporter, role that each of these molecules play in rewarding and drug reinforced behavior remains to be elucidated. Transgenic mice that have been genetically altered to lack a particular gene product provide a powerful means by which to assess the role of that product in vivo. During the preceding funding period we successfully produced three strains of mice that carry mutated D2 or D4 receptor genes. In this competing continuation application we propose to: (1) Breed and test our three mutant mouse strains (N5 D2-/-, N5 D4-/- and D2-/-D4-/-) for their behavioral, physiological and biochemical responses to opiates and psychostimulants; (2) Explore neuronal plasticity at the level of gene expression in our dopamine receptor-deficient mice and relate these findings to drug sensitization; and (3) Develop new mouse strains that carry inducible targeting vectors that will permit the conditional expression of a given dopamine receptor.